How I diagnose and manage VEXAS syndrome.

OBJECTIVES: To discuss VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, including the clinical and pathologic features, diagnostic challenges, and treatment options. METHODS: A case-based approach and pertinent literature review were used to highlight the features of VEXAS syndrome, describe how to make the diagnosis, and discuss available therapies. RESULTS: VEXAS syndrome is an adult-onset, progressive systemic inflammatory disorder with overlapping rheumatologic and hematologic manifestations, including an increased risk of myelodysplastic neoplasms and plasma cell neoplasms. The disorder is associated with a somatic mutation of the X-linked UBA1 gene involved in ubiquitylation, typically involving p.Met41; however, rare variations have been identified outside this region. Patients often present with complex histories and see physicians from multiple specialties before receiving the diagnosis, which is often delayed. Symptoms are related to inflammation as well as cytopenias, particularly macrocytic anemia. Characteristic cytoplasmic vacuoles are present in myeloid (granulocytic, monocytic) and erythroid precursors in the vast majority of cases. CONCLUSIONS: Either clinicians or pathologists may suspect a diagnosis of VEXAS syndrome depending on the clinical presentation and bone marrow findings. More studies are needed to determine the best therapeutic options, which are currently limited.

Blast Phase of Myeloproliferative Neoplasm Resembles Acute Myeloid Leukemia, Myelodysplasia-Related, in Clinical Presentation, Cytogenetic Pattern, and Genomic Profile, and Often Undergoes Reversion to Second Chronic Phase Status After Induction Chemotherapy.

CONTEXT.­: BCR::ABL-negative myeloproliferative neoplasm (MPN) has a prolonged clinical course, and some cases eventually undergo transformation to blast phase; its pathogenesis remains to be elucidated. OBJECTIVE.­: To evaluate the clinicopathologic characteristics of MPN in blast phase. DESIGN.­: The study aimed to retrospectively analyze the clinical and laboratory data of 24 cases. RESULTS.­: Median latency to blast phase was 48 months (range, 7-384 months). Complex karyotypes were seen in 12 of the 24 cases (50%). Overall, 16 cases (66.7%) exhibited high allele burdens of MPN driver mutations along with increased blasts, consistent with linear clonal evolution, whereas the remainder (8; 33.3%) showed loss or partial loss of the driver mutation suggestive of a parallel evolution. Additional mutations were noted in 23 cases (100%), including TP53 mutations in 10 of 24 cases (41.7%). Following chemotherapy, 15 of the 24 patients (62.5%) reverted to a second chronic phase while retaining or regaining MPN driver mutations and losing blast-related mutations, although 9 of the 15 patients (60%) later died of disease progression. Median overall survival was 10 months (CI, 4.6-15.4), with those harboring complex karyotypes demonstrating decreased survival (6 versus 29 months; P = .004). CONCLUSIONS.­: MPN-blast phase resembles acute myeloid leukemia, myelodysplasia-related, in cytogenetic pattern, mutation profile, and clinical outcome. Two patterns of clonal evolution are inferred by dynamic analysis of mutation profiles: linear and parallel evolutions. Although overall survival was dismal, 62.5% of our cases achieved second chronic phase, and they showed better survival than those without second chronic phase.

Primary plasmablastic lymphoma of the gastrointestinal tract: A series of 13 HIV-negative cases and a review of literature.

CONTEXT: Primary gastrointestinal plasmablastic lymphoma (GI-PBL) is a rare variant of diffuse B-cell lymphoma with an aggressive clinical course. PBL was initially reported among HIV-positive patients; however, subsequent studies have shown that it also occurs among HIV-negative patients. Its clinical characteristics remain poorly understood. This study aims to retrospectively analyze the clinicopathological findings of primary GI-PBLs in HIV-negative patients. DESIGN: Primary HIV-negative GI-PBL cases from 2008 to 2022 were reviewed. Clinicopathologic features and outcomes were analyzed. RESULTS: The cohort of 13 patients had a male-to-female ratio of 9:1 (3 patients' genders not available), with an average age of 61 (range, 30-92) years. The most involved location was the colon (n = 7 [53.8 %]), followed by the small bowel (n = 3 [23.1 %]), stomach (n = 2 [15.4 %]), rectum (n = 1 [7.7 %]), and anus (n = 1 [7.7 %]). Most patients (n = 10 [77 %]) showed isolated GI tract involvement. Eight patients had chronic inflammatory and/or immunocompromised status, including 4 with inflammatory bowel disease (all of whom underwent treatment), 3 with post-organ transplant status, and 1 with irritable bowel syndrome. All cases exhibited cytokeratin-/CD20-/PAX-5-/CD138+ and/or MUM1+ immunophenotype. Based on available data, 8 of 11 (72.7 %) patients had Epstein-Barr virus reactivation. Among 11 patients with follow-up data, the mean follow-up duration was 13.5 (range, 3-40) months; at the end of follow-up, 45.5 % of patients (5 of 11 patients) showed complete remission after chemotherapy. CONCLUSION: Primary HIV-negative GI-PBL occurs predominantly in the colon of relatively elderly males with immunosuppression. Its clinical course can be heterogenous, presenting a comorbidity with inflammatory bowel disease or post-organ transplantation status.

Atypical thymic carcinoid tumor with ectopic ACTH syndrome in a 33-year-old male patient: A rare case report and literature review.

RATIONALE: Atypical thymic carcinoid tumor is an exceedingly rare thymic neuroendocrine tumor derived from the cells of neuroendocrine system. Misdiagnosis or delayed diagnosis may result in disease progression to advanced stages and eventually leads to a poor prognosis. It is therefore necessary to make a correct diagnosis and provide an adequate treatment. PATIENT CONCERNS: A 33-year-old Chinese male presented with numbness in bilateral lower extremities and general fatigue for a month. Chest computed tomography revealed a superior anterior mediastinal mass. Thymoma was initially considered, given the location of the mass and radiographic presentation. DIAGNOSIS: Microscopic findings showed that the tumor cells are arranged in pseudoepitheliomatous growth or irregular nested growth pattern in a background of fibroconnective tissue, with focal infiltration into adipose tissue. The chrysanthemum-like structure or beam-like structure seen often in typical carcinoid tumor was not identified in this case. The tumor cells are spindled or oval, with focal active mitosis. The immunohistochemical staining showed strong positivity for CD56, CgA and Syn, positivity for CK, ACTH, and TTF-1, negativity for Vimentin, and ki67 labeled proliferation index was up to 10% in focal areas. According to the radiological and pathological findings, the diagnosis of atypical thymic carcinoid was made. INTERVENTIONS: The patient underwent surgical resection of the mass. OUTCOME: No recurrence or metastasis was identified during the follow up. LESSONS: Because of its low incidencen, onspecific clinical symptoms, tissue location, and radiological findings, atypical thymic carcinoid tumor may sometimes be misdiagnosed as thymoma. Attention should be paid to avoid misdiagnosis.

TRIM56 acts through the IQGAP1-CDC42 signaling axis to promote glioma cell migration and invasion.

Diffuse invasion is an important factor leading to treatment resistance and a poor prognosis in gliomas. Herein, we found that expression of the tripartite motif containing 56 (TRIM56), a RING-finger domain containing E3 ubiquitin ligase, was markedly higher in glioma than in normal brain tissue, and was significantly correlated with malignant phenotypes and a poor prognosis. In vitro and in vivo experimental studies revealed that TRIM56 promoted the migration and invasion of glioma cells. Mechanistically, TRIM56 was transcriptionally regulated by SP1 and promoted the K48-K63-linked poly-ubiquitination transition of IQGAP1 at Lys-1230 by interacting with it, which in turn promoted CDC42 activation. This mechanism was confirmed to mediate glioma migration and invasion. In conclusion, our study provides insights into the mechanisms through which TRIM56 promotes glioma motility, i.e., by regulating IQGAP1 ubiquitination to promote CDC42 activation, which might be clinically targeted for the treatment of glioma.

Chronic Lymphocytic Leukemia With Two B-Cell Populations of Discordant Light Chain Restrictions in Individual Patients: Parallel Development of Biclonal B-Cell Neoplasms or Clonal Evolution With Isotype Switch?

OBJECTIVES: To evaluate clinicopathologic characteristics of biclonal chronic lymphocytic leukemia (CLL). METHODS: Retrospectively analyze clinical data and pathologic features. RESULTS: Ten cases were identified in which flow cytometry demonstrated an abnormal B-cell population with a CLL-like immunophenotype but showed no definitive light chain restriction. All had cytogenetic abnormalities detected, including seven with two CLL-related abnormalities. Four of these showed features suggestive of clonal evolution, all having del(13q) as a "stem-line" abnormality and three showing del(11q) as a "side-line" abnormality. Five (50%) cases demonstrated deleterious NOTCH1 mutations, in contrast to 11.8% in a control group of monoclonal CLL (P < .05). Of the 10 patients, 5 received treatment, with good/partial response in three cases and therapeutic resistance in one case. The median treatment-free survival was estimated at 68 months. CONCLUSIONS: Despite a polytypic pattern of light chain expression, the neoplastic nature of biclonal CLL is suggested by a characteristic CLL phenotype and can be confirmed by cytogenetic and genomic analyses. The two clones with discordant light chain isotypes may share a "stem-line" cytogenetic abnormality, suggesting possible clonal evolution. Biclonal CLL is associated with NOTCH1 mutations, which may occur in a small subclone and gradually evolve in clonal size. Genomic analysis on light chain-sorted and/or chronologically collected samples may provide insight into clonal evolution in CLL.

Endometrioid adenofibroma of ovary: A case report and review of literature.

RATIONALE: Endometrioid adenofibroma is a benign epithelial neoplasm of the ovary, most of which are often unilateral. The symptoms of endometrioid adenofibroma are often nonspecific and misleading. Therefore, a full understanding of the characteristics, diagnosis, and treatment methods of this disease is of great importance. In this study, we report a 34-year-old woman who was found with an unidentified mass on the right ovary during the physical examination 3 years ago with nosymptoms or signs. PATIENT CONCERNS: A 34-year-old Chinese female was found with an unidentified 6 cm mass on the right ovary for 3 years that presented with no symptoms or signs. DIAGNOSIS: Pelvic ultrasound revealed a 6 cm cystic solid mixed mass on the right ovary. Through histological and immunohistochemical examinations, the tumor mass was finally diagnosed as endometrioid adenofibroma of ovary. INTERVENTIONS: To confirm the diagnosis, the ovarian tumor was laparoscopically resected. OUTCOMES: The patient returned to hospital after 3 months with no recurrence or postoperative complications. LESSONS: Endometrioid adenofibroma is a benign epithelial neoplasm of the ovary. Complete surgical resection is required and rare cases can recur. Postsurgical pathologic and immunohistochemical testing can confirm a diagnosis of endometrioid adenofibroma. It is important to understand of the key points of differential diagnosis of the disease due to the different prognosis and clinical treatment.

Clinical Response to Upfront Targeted Tyrosine Kinase Inhibitors among Patients with Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusion.

INTRODUCTION: Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusion (MLN-TK) is an entity encompassed of a heterogeneous group of rare hematopoietic neoplasms that are driven by gene fusion involving PDGDRA/B, FGFR1, JAK2, FLT3 or ETV6::ABL1. Though patients presenting with chronic phase MLN-TK with PDGFRA fusion display a favorable outcome in response to upfront TK inhibitor (TKI) therapy, the outcomes of MLNs driven by other TK fusions are not well described. In this study, we aimed to critically analyze the treatment outcomes of patients with MLN-TK, focusing on the role of upfront TKIs in both chronic- and blast-phase diseases. METHODS: The retrospective study included patients with confirmed MLN-TK from 3 centers and assessed demographic and clinical variables, treatment, and outcomes. RESULTS: Forty-two patients with confirmed MLN-TK [PDGFRA (n = 22), PDGFRB (n = 4), FGFR1(n = 10), JAK2 (n = 2); and FLT3 (n = 3)] were included. Fifteen of 25 (60%) chronic-phased patients received upfront TKI therapy had a long-term remission. Nine of 16 (60%) blast-phase patients with upfront TKIs also achieved complete remission and remained alive at a median follow-up of 20 months. All 3 patients with blast phase disease who received upfront chemotherapy without positive response did not respond to subsequent TKI therapy, emphasizing the importance of initiating TKI therapy early. Upfront TKI therapy was associated with longer overall survival in univariate analyses (HR, 0.054 [95% CI, 0.007-0.42]) and multivariate analyses (HR, 0.03 [95% CI, 0.002-0.47]). CONCLUSION: The outcomes of upfront TKI therapy are excellent for MLN-TK in both chronic and blast phases, regardless of gene abnormalities.

PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo.

Many patients with multiple myeloma (MM) have comorbidities and are treated with PPAR agonists. Immunomodulatory agents (IMiDs) are the cornerstones for MM therapy. Currently, little is known about how co-administration of PPAR agonists impacts lenalidomide treatment in patients with MM. Here, we determined the effects of PPAR agonists on anti-myeloma activities of lenalidomide in vitro and in a myeloma xenograft mouse model. Genetic overexpression and CRISPR/cas9 knockout experiments were performed to determine the role of CRBN in the PPAR-mediated pathway. A retrospective cohort study was performed to determine the correlation of PPAR expression with the outcomes of patients with MM. PPAR agonists down-regulated CRBN expression and reduced the anti-myeloma efficacy of lenalidomide in vitro and in vivo. Co-treatment with PPAR antagonists increased CRBN expression and improved sensitivity to lenalidomide. PPAR expression was higher in bone marrow cells of patients with newly diagnosed MM than in normal control bone marrow samples. High PPAR expression was correlated with poor clinical outcomes. Our study provides the first evidence that PPARs transcriptionally regulate CRBN and that drug-drug interactions between PPAR agonists and IMiDs may impact myeloma treatment outcomes.

Intra-tumoral angiogenesis correlates with immune features and prognosis in glioma.

Gliomas are the most common malignant tumor in the brain. As with other tumors, the progression of glioma depends on intra-tumoral angiogenesis. However, the effect of angiogenesis on gliomas is still not fully understood. In this study, we developed an angiogenesis pathway score using Gene Set Variation Analysis (GSAV) in R to assess the status of intra-glioma angiogenesis in The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA mRNAseq_325, CGGA mRNA-array), and GSE16011 datasets. We found that the angiogenesis pathway score not only accurately predicted the prognosis of glioma patients, but also accurately distinguished the malignant phenotype and immune characteristics of gliomas. In addition, as an independent prognostic factor, the score could predict glioma sensitivity to radiotherapy and chemotherapy. In summary, we used the angiogenesis pathway score to reveal the relationship between glioma angiogenesis and the malignant phenotype, immune characteristics, and prognosis of glioma.

Human herpesvirus 8-negative effusion-based large B-cell lymphoma: a distinct entity with unique clinicopathologic characteristics.

Rare cases of human herpesvirus 8 (HHV8)-negative effusion-based large B-cell lymphoma (EB-LBCL) occur in body cavities without antecedent or concurrent solid mass formation. In contrast to HHV8 + primary effusion lymphoma (PEL), EB-LBCL has no known association with HIV or HHV8 infection. However, the small sample sizes of case reports and series worldwide, especially from non-Japanese regions, have precluded diagnostic uniformity. Therefore, we conducted a retrospective, multi-institutional study of 55 cases of EB-LBCL and performed a comprehensive review of an additional 147 cases from the literature to identify distinct clinicopathologic characteristics. In our study, EB-LBCL primarily affected elderly (median age 80 years), immunocompetent patients and manifested as lymphomatous effusion without a solid component. The lymphomatous effusions mostly occurred in the pleural cavity (40/55, 73%), followed by the pericardial cavity (17/55, 31%). EB-LBCL expressed CD20 (53/54, 98%) and PAX5 (23/23, 100%). Most cases (30/36, 83%) were of non-germinal center B-cell subtype per the Hans algorithm. HHV8 infection was absent (0/55, 0%), while Epstein-Barr virus was detected in 6% (3/47). Clinically, some patients were managed with drainage alone (15/34, 44%), while others received rituximab alone (4/34, 12%) or chemotherapy (15/34, 44%). Eventually, 56% (22/39) died with a median overall survival (OS) of 14.9 months. Our findings were similar to those from the literature; however, compared to the non-Japanese cases, the Japanese cases had a significantly higher incidence of pericardial involvement, a higher rate of chemotherapy administration, and longer median OS. Particularly, we have found that Japanese residence, presence of pericardial effusion, and absence of MYC rearrangement are all favorable prognostic factors. Our data suggest that EB-LBCL portends a worse prognosis than previously reported, although select patients may be managed conservatively. Overall, EB-LBCL has distinct clinicopathologic characteristics, necessitating the establishment of separate diagnostic criteria and consensus nomenclature.

The hypereosinophilic syndrome - an unusual cause of myocarditis and cardioembolic strokes.

Hypereosinophilic syndrome is a rare disorder characterized by excessive peripheral eosinophilia and eosinophil associated end-organ damage. Clinical presentations are heterogenous and can involve skin, pulmonary, cardiac and neurologic dysfunction. Eosinophilic myocarditis is a life-threatening complication that increases the risk of cardiac microemboli, which can subsequently lead to embolic strokes. Secondary to changes in blood viscosity, impaired clearance of microemboli, impaired cerebral blood flow, and pro-thrombotic conditions in the setting of hypereosinophilia, infarcts often present in vascular border zone regions. Here we present two cases of cardioembolic strokes involving borderzone regions in the setting of hypereosinophilic syndrome.

Update on the Classification of and Diagnostic Approaches to Mature T-Cell Lymphomas.

CONTEXT.­: In the 2017 revised World Health Organization classification of tumors of hematopoietic and lymphoid tissues, some mature T-cell lymphomas were reclassified and a few new provisional entities were established based on new data from clinical and laboratory studies. T follicular helper cell lymphoma is identified by T follicular helper cell markers. Anaplastic large cell lymphoma, ALK negative, is a better-defined entity based on genetic abnormalities, and breast implant-associated anaplastic large cell lymphoma is recognized as a provisional entity. The gastrointestinal T-cell lymphomas are reclassified, with addition of a new provisional entity, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, characterized by an indolent clinical course. OBJECTIVE.­: To review the diagnostic approaches to reclassified and newly established entities of mature T-cell lymphomas, focusing on significant immunophenotypic features and molecular genetic abnormalities. Relevant new discoveries after the publication of the 2017 World Health Organization classification are included. DATA SOURCES.­: Information from the literature most relevant to the 2017 World Health Organization revised classification and publications after 2016. CONCLUSIONS.­: Incorporating clinical, morphologic, and immunophenotypic features usually provides sufficient evidence to reach a preliminary diagnosis of mature T-cell lymphoma. Molecular genetic studies can be very helpful for the final diagnosis and classification, especially in challenging cases. Some molecular genetic features have been found in breast implant-associated anaplastic large cell lymphoma, distinct from anaplastic large cell lymphoma, ALK negative. Immunohistochemical staining of 4 markers may enable further subtyping of peripheral T-cell lymphomas.

Sequential Development of JAK2V617F Mutation and BCR-ABL1 Fusion in Individual Patients With Myeloproliferative Neoplasms.

CONTEXT.­: Concomitant BCR-ABL1 and JAK2V617F in myeloproliferative neoplasms (MPNs) is rare, and its pathogenesis and clinical significance are unclear. OBJECTIVE.­: To investigate the clonal relationship between the 2 genomic alterations, as well as the clinicopathologic impact. DESIGN.­: Retrospective analysis of MPNs with sequential development of BCR-ABL1 and JAK2V617F. RESULTS.­: Of 6 cases, 5 had JAK2V617F-positive MPN diagnosed before acquiring BCR-ABL1 years later, and 1 had BCR-ABL1+ chronic myeloid leukemia before JAK2V617F-positive myelofibrosis completely replaced the BCR-ABL1+ clone 1 year after tyrosine kinase inhibitor therapy. Among the former group, treatment for the initial MPN involved hydroxyurea, ruxolitinib, and/or supportive care, and the latency to the development of JAK2V617F ranged from 4 to 13 years (median of 9 years). Four cases showed retention of JAK2V617F, whereas BCR-ABL1 emerged as the major clone, including 2 cases that exhibited parallel increases in JAK2V617F and BCR-ABL1 burdens, with both genomic markers exceeding 50%. Three patients received stem cell transplants and demonstrated sustained engraftment, with the genomic markers below detectable levels. CONCLUSIONS.­: Most MPNs with concomitant JAK2V617F and BCR-ABL1 are actually composite MPNs with a "second hit" residing on a different clone. Rare cases demonstrate a subclone harboring a "double-hit" in a background of a JAK2V617F-positive stem line clone. The probability of a "double-hit" with a BCR-ABL1+ stem line clone is probably reduced by effective tyrosine kinase inhibitor treatment. The treatment often involves combined kinase inhibitors and/or hydroxyurea, but the outcome is unpredictable; hematopoietic stem cell transplantation may be the ultimate therapeutic option for this complicated disease.